Abstract Multiple Hereditary Exostoses (MHE) is an autosomal dominant disorder that affects about 1 in 50,000 children. MHE (also known as Hereditary Multiple Exostoses or Multiple Osteochondromas) is characterized by cartilaginous outgrowths called exostoses that develop adjacent to the growth plates of skeletal elements, impinge onto surrounding tissues and cause: compression of nerves and tendons with consequent pain and impairment of motion; chronic pain; skeletal deformities; and early onset osteoarthritis. They become malignant in about 2% of the patients. Current therapies are palliative, and patients struggle with pain and limited mobility and undergo multiple surgeries through life. MHE is caused by loss-of-function mutations in EXT1 and EXT2 that are responsible for heparan sulfate synthesis, and patients display varying degrees of heparan sulfate deficiency. Heparan sulfate chains regulate a significant number of critical physiologic processes, accounting for the multitude of symptoms and health problems from which MHE patients suffer throughout their life. Because of such complexity, the understanding of MHE and finding a cure require multifaceted approaches that involve genetics, enzymology, glycobiology, developmental biology, and orthopedics, and an exchange of ideas and the establishment of collaborative efforts among various disciplines. Hence, the key objective of the Forth International MHE Research Conference is to bring together physicians, physicians-scientists and scientists who study MHE and care for MHE patients and additional scientists who work in closely related fields, including skeletal development and growth, human genetic skeletal diseases, drug discovery, and mammalian and non-mammalian animal models of human diseases. In addition to being at the forefront of research in their fields, the invited speakers have diverse expertise and perspectives. Thus, the Conference will serve as a timely and vigorous forum for the exchange of the most recent data, will generate new ideas, approaches and hypotheses about the pathogenesis of MHE, and will promote further interactions amongst researchers in different fields. The Conference will be held at the In at Penn at the University of Pennsylvania in Philadelphia on November 1-4, 2012, will have eight sessions on MHE clinical manifestation and orthopaedics, human genetics, developmental biology, heparan sulfate chemistry, animal disease models and related bone diseases, and about 50 participants (including over 3o invited speakers and non-speaking discussants). Each session will have three to four speakers who will present 20-minute talks followed by 10 minutes of discussion. The format, roster, and size of the meeting are designed to maximize interactions among participants in an informal setting. Because of the encompassing roles of heparan sulfate in human physiology, the Conference will have broad and far-reaching impact and relevance for both basic research and translational and clinical medicine. As importantly, it will provide a renewed sense of hope to patients and families alike that MHE is being actively studied and a cure will one day be found. PUBLIC HEALTH RELEVANCE: Narrative Multiple hereditary exostoses is a debilitating genetic disorder characterized by the formation of multiple bony protrusions that cause a significant number of symptoms and pathological consequences This conference aims to promote the exchange of the most current information regarding MHE and the collaboration and synergy among laboratories studying this disease. This goal will be accomplished by bringing together world experts in the fields of orthopedics, human genetics, developmental biology, glycobiology, and related human bone diseases, and by providing them with a highly focused forum to cultivate new ideas, foster cross-discipline collaborations, discover the pathogenesis of the disease and begin to envision possible ways to treat it.